Idiopathic pulmonary fibrosis (IPF) is an aging-related progressive fatal lung disorder with no known etiology and no effective treatment. Alveolar type II epithelial cell (AEC2) apoptosis and (myo)fibroblast apoptosis resistance are evident in IPF lungs and are believed to be a key in the initiation and progression of IPF. Interestingly, our studies show that old mice experience diminished fibroblast apoptosis but augmented AEC2 apoptosis and fibrotic response upon bleomycin challenge, compared to young mice, suggesting that dysregulation of AEC2 and fibroblast apoptosis may underlie the aging-related susceptibility to IPF. The mechanism underlying the dysregulation of fibroblast and AEC2 apoptosis during aging, however, is unknown. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators (tPA and uPA), plays an important role in the development of lung fibrosis. Importantly, our previous studies/preliminary data show that PAI-1 expression is increased with age in mouse lung fibroblasts and AEC2 and that inhibition of PAI-1 activity restored the sensitivity of lung fibroblasts from old mice to apoptosis. Our previous studies/preliminary data further show that inhibition of PAI-1 activity or knockdown of PAI-1 with PAI-1 siRNA induces p53, a master controller of apoptosis, and apoptosis in lung fibroblasts but suppresses p53 and apoptosis in AEC2. Based on these data, we hypothesize that aging-related increase in PAI-1 leads to dysregulation of AEC2 and fibroblast apoptosis, which underlies the increased susceptibility of the elderly to lung fibrosis. Redox imbalance is evident in aged animals and in IPF. How redox imbalance contributes to aging-related susceptibility to IPF, however, is unclear. Our previous studies/preliminary data show that the concentrations of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, decrease whereas the expression of NADPH oxidase 4 (Nox4), an important producer of reactive oxygen species (ROS), increases with age in rodent lungs. Our previous studies also showed that Nox4-derived ROS induced PAI-1 in fibroblasts through modifying/inhibiting MAPK phosphatase 1 (MKP-1) whereas GSH selectively inhibited TGF-?1-induced PAI-1 by blocking JNK/p38 activation. Importantly, our preliminary data show that MKP-1 thiol modification is increased whereas the activity of MKP-1 is decreased in the lung of old mice. Therefore, we further hypothesize that aging-related redox imbalance contributes to the dysregulation of AEC2 and fibroblast apoptosis through inducing PAI-1 by modifying/inhibiting MKPs (e.g. MKP-1). Four specific aims are proposed to test our hypotheses, using different animal models including novel PAI-1 conditional knockout mouse models recently generated in this lab. The therapeutic potential of a small molecule PAI-1 inhibitor for lung fibrosis will also be tested in aged mice. The results from these studies will nt only shed new light on the mechanism underlying aging-related susceptibility to IPF but may also lead to novel paradigm shifting concept as well as new therapeutics for the treatment of IPF.